-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-[5-[N-[5-[N-[5-[N-(2-Amidinoethyl)carbamoyl]-1-methyl-1H-pyrrol-3-yl]carbamoyl]-1-methyl-1H-pyrrol-3-yl]carbamoyl]-1-methyl-1H-pyrrol-3-yl]-3-[8-(chloromethyl)-4-hydroxy-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indazol-6-ylcarbonyl]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride

【CA登记号】

【分子式】C₃₈H₄₂Cl₂N₁₄O₆

【分子量】861.75464

【开发单位】Rega Institute for Medical Research (Originator), Tokyo Medical and Dental University (Originator), Università di Ferrara (Originator)

【药理作用】Oncolytic Drugs, DNA-Damaging Drugs

合成路线1 合成路线2

合成路线1

The pyrazoledicarboxylic acid mono-methyl ester (I) was converted to the methyl benzyl diester (II) by treatment with benzyl bromide in the presence of DBU. Selective hydrolysis of the methyl ester function with KOH then provided the carboxylic acid (III). Coupling of acid (III) with deformyl distamycin A (IV) using EDC and HOBt gave amide (V). The protecting benzyl ester group of (V) was cleaved by catalytic hydrogenation over Pd/C to yield acid (VI). Amine (VIII) was obtained by acid cleavage of the Boc group from the protected precursor (VII). Subsequent coupling of amine (VIII) with carboxylic acid (VI) furnished the title compound.

参考文献中间体

【1】 Baraldi, P.G.; et al.; Design, synthesis, DNA binding, and biological evaluation of water-soluble hybrid molecules containing two pyrazole analogues of the alkylating cyclopropylpyrroloindole (CPI) subunit of the antitumor agent CC-1065 and polypyrrole minor groove binders. J Med Chem 2001, 44, 16, 2536.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	51295	5-(methoxycarbonyl)-1-methyl-1H-pyrazole-3-carboxylic acid	C₇H₈N₂O₄	详情	详情
(II)	51296	3-benzyl 5-methyl 1-methyl-1H-pyrazole-3,5-dicarboxylate	C₁₄H₁₄N₂O₄	详情	详情
(III)	51297	3-[(benzyloxy)carbonyl]-1-methyl-1H-pyrazole-5-carboxylic acid	C₁₃H₁₂N₂O₄	详情	详情
(IV)	26888	N-(3-amino-3-iminopropyl)-4-[[(4-[[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrole-2-carboxamide	C₂₁H₂₇N₉O₃	详情	详情
(V)	51298	benzyl 5-[[(5-[[(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrazole-3-carboxylate	C₃₄H₃₇N₁₁O₆	详情	详情
(VI)	51299	5-[[(5-[[(5-[[(5-[[(3-amino-3-iminopropyl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrrol-3-yl)amino]carbonyl]-1-methyl-1H-pyrazole-3-carboxylic acid	C₂₇H₃₁N₁₁O₆	详情	详情
(VII)	51300	tert-butyl 8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydropyrrolo[3,2-e]indazole-6(3H)-carboxylate	C₁₆H₂₀ClN₃O₃	详情	详情
(VIII)	51301	8-(chloromethyl)-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indazol-4-ol	C₁₁H₁₂ClN₃O	详情	详情

合成路线2

The methylation of 6-chloro-1H-indole-2-carboxylic acid ethyl ester (I) with NaH and Me-I in DMF gives the 1-methylindole derivative (II), which is condensed with 2-chloro-2-oxoacetic acid ethyl ester (III) by means of TiCl4 in dichloroethane to yield 6-chloro-2-[2-(ethoxycarbonyl)-1-methyl-1H-indol-3-yl]-2-oxoacetic acid ethyl ester (IV). The cyclization of (IV) with phenylhydrazine (V) in refluxing acetic acid affords the 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylic acid ethyl ester (VI). The reduction of the ester group of (VI) by means of NaBH4 in refluxing THF/methanol affords the hydroxymethyl derivative (VII), which is oxidized with MnO2 in refluxing dichloromethane to provide the corresponding carbaldehyde (VIII). The reaction of (VIII) with p-Toluenesulfonylmethyl isocyanide (TosMIC) and potassium tert-butoxide in dimethoxyethane gives the acetonitrile derivative (IX), which is hydrolyzed with HCl in refluxing methanol to yield the acetate ester derivative (X). Finally, this compound is treated with dimethylamine and trimethylaluminum in toluene to afford the target dimethylacetamide derivative.

参考文献中间体

【1】 Bartsch, R.; Sevrin, M.; Froissant, J.; Evanno, Y.; Dubois, L.; Marguet, F.; Gille, C. (Sanofi-Synthélabo); 4-Oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetamide derivs., their preparation and their application in therapy. EP 1000063; FR 2766823; JP 2001512122; US 6262045; WO 9906406 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	55771	ethyl 6-chloro-1H-indole-2-carboxylate		C₁₁H₁₀ClNO₂	详情	详情
(II)	55772	ethyl 6-chloro-1-methyl-1H-indole-2-carboxylate		C₁₂H₁₂ClNO₂	详情	详情
(III)	11043	Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride	4755-77-5	C₄H₅ClO₃	详情	详情
(IV)	55773	ethyl 6-chloro-3-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-indole-2-carboxylate		C₁₆H₁₆ClNO₅	详情	详情
(V)	11818	Phenyl hydrazine; 1-Phenylhydrazine	100-63-0	C₆H₈N₂	详情	详情
(VI)	55774	ethyl 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate		C₂₀H₁₆ClN₃O₃	详情	详情
(VII)	55775	7-chloro-1-(hydroxymethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one		C₁₈H₁₄ClN₃O₂	详情	详情
(VIII)	55776	7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carbaldehyde		C₁₈H₁₂ClN₃O₂	详情	详情
(IX)	55777	2-(7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)acetonitrile		C₁₉H₁₃ClN₄O	详情	详情
(X)	55778	methyl 2-(7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)acetate		C₂₀H₁₆ClN₃O₃	详情	详情
(XI)	19443	N-methylmethanamine; N,N-dimethylamine	124-40-3	C₂H₇N	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)